Disclosures and Funding. Racial-Ethnic Association with QT Prolongation Following Acute Drug Overdose. Acute Drug Overdose.

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1 Racial-Ethnic Association with QT Prolongation Following Acute Drug Overdose EAPCCT Dubrovnik, Croatia May 2011 Alex F. Manini, MD, MS Division of Medical Toxicology Mount Sinai School of Medicine New York, NY, USA Disclosures and Funding No commercial disclosures to report PI is supported by a Career Development Award (K23) from NIH/NIDA QT Interval Electrical depolarization and repolarization of the left and right ventricles Sodium, calcium and potassium current Varies with heart rate faster heart rate shorter the QT interval Must be corrected (QTc) Determinants of QT Interval Factors associated with baseline QT interval Race (whites 5-10ms 5 > blacks) Genetic (chromosome 7 and 11) Gender (females 10ms > males) Age (increase trend) Role of above factors in drug-induced QT changes Extrapolation unclear: Therapeutic v OD? Baseline v Drug-induced? Lehmann JACC 1997 Vitelli Am J CArdiol 1998 Myocardial Sensitization QT Risk Categories: Acute Drug Overdose Altered substrate Undifferentiated acute drug overdoses Normal QTc Long QTc (but <500 ms) Severe QTc 500 ms Triggered event Risk of CV events Shock MI VT/VF Cardiac Arrest Lowest Risk 3.8% High Risk 26% Highest Risk >38% Nelson LS, J Toxicol Clin Toxicol 2002 Manini AF J Med Toxicol 2009

2 Study Objectives Aim: To evaluate the association between: Race/Ethnicity Drug-induced QT prolongation Target Population: ED patients with acute drug overdose Study Methods Design: Cross sectional observational study over a 2 year period Setting: Urban teaching hospitals Subjects: : Adult ED patients with acute drug overdose, racially diverse Data: Demographics, race/ethnicity, drug class, QTc Definitions Race-ethnicity ethnicity by chart (facesheet and ECG) (a) Race (4 codes): : White, Black, Asian, or other (b) Ethnicity (2 codes): : Hispanic or not Outcome = Prolonged QTc Initial ECG computer generated QTc (Bazzett) 460 ms (men) or 470 ms (women) Statistical Analysis Factors associated with QT prolongation were assessed with chi-squared, t-test, t test, and logistic regression analysis Sample Size: 20% risk factor prevalence 10% QT prolongation Need 466 patients (80% power, 2-fold 2 RD) Results: Enrollment QT prolongation occurred in 11.7% 95% CI = Race Racial-ethnic Composition 38% White 21% Black 10% Asian 31% other Hispanic Ethnicity 196 Hispanic 64% Other-Hispanic 34% Uncoded-Hispanic 2% White-Hispanic

3 Race/ Ethnicity: Results Prolonged QTc Univariate Adjusted * OR CI OR CI Hispanic Black * Model included significant co-variates: age, heart rate, and serum potassium. Asians, White both non-significant. Abbreviations: bpm = beats per min; CI = confidence interval, OR = odds ratio DRUGS CORRELATED WITH QT PROLONGATION Drugs / Drug Class: # Single # Multi-drug # Total Opioids 15 (40) 69 (19) 84 (23) Methadone** 4 (0) 31 (26) 35 (23) methadone 11 (55) 38 (13) 49 (22) Sympathomimetics 10 (60) 48 (15) 58 (22) Antidepressants 8 (38) 39 (5) 47 (11) Citalopram** 0 10 (0) 10 (0) TOTALS 279 (13) 263 (10) 542 (12) Indicates p < 0.05 denoted in BOLD. Drugs not correlated: benzos, OTC, DPH, antiphsychotics, quetiapine, anticonvulsants. ** CERT Drug = Appears on list from the AZ Center for Education and Research on Therapeutics. Abbreviations: QTP = QT prolongation (460 ms male, 470 ms female). Goodness of fit (Pearson) both p > 0.05 Drug Class QT Risk Within Race/Ethnicity Characteristic: No. HISPANIC 196 (8.7) OR P value Multidrug Overdose 17 (100) <0.001 Opioids 37 (30) 10.7 <0.001 Methadone 14 (40) 5.2 <0.05 Methadone 23 (30) 7.1 <0.001 BLACK 78 (19.2) Multidrug Overdose 15 (100) <0.001 Abbreviations: CI = confidence interval, OR = odds ratio; QTP = QT Prolongation Discussion Race/ethnicity highly correlated with QT risk Blacks > 2.5-fold increased QT prolongation (QTP) Hispanics had >50% reduction in QTP risk Vulnerability to QTP in multidrug overdose Genetic vulnerability or vice versa? Major concern in Black population: Shorter QT baseline Higher QTP following overdose Discussion Further evidence of QTP in opioid OD Not just methadone! Non-methadone opioids highly significant correlation with QTP in single-drug OD Novel finding: Hispanics highly vulnerable Lack of CERT QT drugs surprising? Therapeutic dose extrapolate to OD? Not well represented Limited utility for poisoning? Limitations Baseline ECG Drug-induced vs. Congenital Long QT syndrome Not self-reported 5-10% inaccuracy in literature Exposure confirmation incomplete Sedative use for agitation Urban diverse setting May not generalize to all settings

4 Conclusions In this large urban study of acute drug overdose, race/ ethnicity predicted QT prolongation: Blacks had over fold increased risk Highly vulnerable to multidrug OD Hispanics had over 50% risk reduction Highly vulnerable to opioids, multidrog OD Conclusions (continued) We identified high/low risk drug classes Opioids including non-methadone subgroup Sympathomimetics Unable to implicate CERT QT drugs Ongoing Study To explore racial QT risk in drug overdose: Drug class associations Adverse cardiovascular outcomes Genetic polymorphisms Thank You Barry Stimmel MD Cardiology Division Mount Sinai School of Medicine New York, NY USA DavidVlahov PhD Dean, UCSF School of Nursing San Francisco, CA USA. Sensitivity Analysis Assuming up to 10% race misclassification 12% QT prolongation in dataset Hispanics OR 0.62 (CI ) p=0.05 Blacks OR 1.9 (CI ) p<0.05

5 Severe QT Prolongation (>500) 8/15 (53%) multi-drug overdose 6/15 (40%) 1 1 CERT drug Numbers of occurrences: 1/15: : 15 drugs (two CERT 3, one CERT 2) 2/15: : Alprazolam, APAP, cocaine, diazepam 3/15: : Methadone (CERT 1) Class by AZ CERT 1- Highest Risk 2- Possible Risk 3- Conditional Risk DRUGS NOT CORRELATED WITH QT PROLONGATION Drugs / Drug Class: # Single OD # Multi OD # Total Benzodiazepines 10 (20) 75 (13) 85 (14) OTC Drugs 16 (19) 55 (5) 71 (8) Diphenhydramine** 12 (8) 16 (6) 28 (7) Antipsychotics 11 (18) 39 (5) 50 (8) Quetiapine** 5 (0) 22 (9) 27 (7) Anticonvulsants 7 (14) 19 (0) 26 (4) TOTALS 279 (13) 263 (10) 542 (12) ** AZ CERT Drug = Appears on QT-drug list from the Arizona Center for Education and Research on Therapeutics available at Abbreviations: OTC = over the counter ; QTP = QT prolongation.